Interferon Alpha and Omega Antibody Antagonists

Abstract

Broadly neutralizing interferon-α and interferon-ω antibody antagonists, polynucleotides encoding the antibodies or fragments, and methods of making and using the foregoing are usefule in the treatment of diseases associated with increased production of IFNα and IFNω.

We claim: 
     
         1 ) An isolated monoclonal antibody that binds human interferon omega (IFNω) at least at residues R22, R23, I24, S25, P26, F27, L30, K31, D32, R33, R34, D35, Q40, K134, M146, E147, M149, K150, F153 and L154 of SEQ ID NO: 1, and at least one IFNα4a residue selected from the group consisting of A19, G22, R23, I24, S25, H26, F27, C29, L30, K31, D32, R33, H34, D35, V143, A146, E147, M149, R150 and S153 of SEQ ID NO: 19, wherein the antibody neutralizes an activity of IFNαA, IFNαH2, IFNαK, IFNαWA, IFNα4a, IFNω, IFNαB2, IFNαC, IFNαF, IFNαG and IFNαJ1 and the antibody does not bind or neutralize human IFNαD. 
     
     
         2 ) The antibody of  claim 1 , wherein the activity is inhibition of secreted embryonic alkaline phosphatase (SEAP) expression under the interferon inducible ISG54 promoter in HEK293 cells stably expressing signal transducer and activator of transcription 2 (STAT2), interferon regulatory factor 9 (IRF9) and SEAP. 
     
     
         3 ) The antibody of  claim 2 , wherein the antibody neutralizes the activity of IFNω with an IC 50  value of between about 0.9×10 −9  M and about 1.85×10 −8  M. 
     
     
         4 ) The antibody of  claim 3 , wherein the antibody binds IFNω with a dissociation constant (K D ) of between about 0.3×10 −9  M and about 4.5×10 −9  M, wherein the K D  is measured using SPR technology with ProteOn (Bio-Rad Hercules, Calif.), with antibody loaded on an antibody coupled chip for 2 minutes at a flow rate of 30 μl/min, washing with running buffer for 2 minutes at a flow rate of 50 μl/ml, and associating recombinant IFN proteins at 5 different concentrations ranging from 100 nM to 1.23 nM with 1:3 dilution were for 3 minutes and dissociating for 10 minutes, both at the flow rate of 50 μl/ml. 
     
     
         5 ) An antibody that binds human interferon omega (IFNω), wherein the antibody competes for binding to IFNω and IFNα subtypes IFNαB2, IFNαF, IFNαG and/or IFNαJ1 with an isolated antibody. comprising:
 a) a heavy chain variable region (VH) amino acid sequence of SEQ ID NO: 23 and a light chain variable region (VL) amino acid sequence of SEQ ID NO: 24; or 
 b) a VH amino acid sequence of SEQ ID NO: 27 and a VL amino acid sequence of SEQ ID NO: 28. 
 
     
     
         6 ) The antibody of  claim 1 , wherein the antibody inhibits an activity of viral-induced leukocyte interferon, wherein the activity of viral-induced leukocyte interferon is IP-10 release in whole blood induced by 100 U/ml of interferon. 
     
     
         7 ) The antibody of  claim 6 , wherein the activity is inhibited by more than 50% in the presence of 50 μg/ml antibody. 
     
     
         8 ) The antibody of  claim 1 , wherein the antibody does not bind or neutralize human interferon-β (IFNβ). 
     
     
         9 ) The antibody of  claim 8 , wherein the antibody is human, humanized or human-adapted. 
     
     
         10 ) The antibody of  claim 9 , wherein the antibody is of IgG1, IgG2, IgG3 or IgG4 isotype. 
     
     
         11 ) The antibody of  claim 10 , wherein the antibody is bispecific. 
     
     
         12 ) The antibody of  claim 11 , wherein the antibody binds BLyS, CD40L, IL-6, CD27, BDCA2 or the p40 subunit of IL-12 or IL-23. 
     
     
         13 ) A pharmaceutical composition comprising the antibody of  claim 1  and a pharmaceutically accepted carrier.